Human neuropsychology and monkey ablation studies show that the prefrontal cortex (PFC) is involved in affect, social behavior as well as executive functions such as working memory and decision-making. Dysfunction of the PFC is associated with neuropsychiatric disorders including schizophrenia, autism and depression. Given the developmental origin of many of these disorders, it is crucial to understand the mechanisms of generation, specification and differentiation of PFC neurons during normal development. Despite the recent advances in the studies of neocortical development, how much of the findings on other parts of the neocortex is applicable to the PFC has remained unknown. Region-specific developmental programs of the neocortex have been studied extensively in recent years. These include intrinsic patterning mechanisms that confer positional identity to neural progenitor cells, as well as the extrinsic influences by thalamic afferents. A majority of research in this field, especially the studies on the extrinsic roles of the thalamus in regional development of the neocortex, has focused on primary sensory areas, while little attention has been paid to the PFC. In order to elucidate the developmental mechanisms of the PFC with molecular genetic approaches, we have identified genes whose expression patterns delineate early postnatal PFC areas. We then analyzed the expression of these genes in mutant mice that lack thalamus-PFC connections, and found a profound change that predicts an altered retinoid signaling in the PFC. Based on these preliminary data, we propose to study the roles of the thalamus and retinoid signaling in PFC development. Abnormal development of the thalamic nuclei that project axons to the PFC as well as abnormal retinoid signaling in the PFC are both implicated in the pathogenesis of developmental brain disorders. However, molecular and cellular basis of such correlations have remained largely elusive. Our proposed research will be a first step to a better understanding of these important questions.